Despite the success of lipid lowering drugs for the prevention of coronary artery disease and myocardial infarction, atherosclerosis remains the most common cause of disease-related death in the Western world and in developing countries. We and others have demonstrated that histone deacetylase inhibitors (HDIs) have anti-inflammatory effects and can be used to treat certain chronic inflammatory diseases. Given the inflammatory component of atherosclerosis, and based on our preliminary data, the hypothesis to be tested in this proposal is that histone deacetylase 9 (HDAC9) plays an important role in the pathogenesis of atherosclerosis by regulating the expression of lipid homeostatic and inflammatory genes in macrophages. Our long term goal is to develop selective HDIs for the treatment and prevention of atherosclerosis. Three specific aims are proposed. Specific Aim 1 will test the hypothesis that inactivation of HDAC9 in macrophages will decrease, and overexpression will increase atherosclerosis in Ldlr -/- mice by modifying lipid homeostatic and inflammatory genes in vivo. We will do bone marrow transplant from HDAC9 deficient and HDAC9 transgenic mice to Ldlr-/- mice and determine its effect on atherosclerosis. The Specific Aim 2 will test the hypothesis that HDAC9 mediates lipid homeostasis by modulating cholesterol efflux and influx pathways in macrophages. We will use thioglyocollate-elicited peritoneal macrophages or bone marrow derived macrophages to study the effect of different levels of expression of HDAC9 on cholesterol efflux (ABCA1, ABCG1, and SR-B1 mediated), cholesterol esterification, and lipoprotein binding and degradation. Specific Aim 3 will test the hypothesis that HDAC9 activity regulates inflammation in macrophages. We will perform transendothelial migration, chemotaxis, and adhesion assays using macrophages expressing different amounts of HDAC9. Fluorescent or radiolabeled macrophages will be used to monitor monocyte- macrophage homing to atherosclerotic plaques in vivo. We will also measure cytokine, chemokines, integrins and adhesion molecules in macrophages expressing different amount of HDAC9 upon IPS stimulation. This study will provide new insight into the mechanisms by which HDAC9 plays a role in the pathogenesis of atherosclerosis. Ultimately, this study may provide the foundation for the development of specific histone deacetylase inhibitors that only targets HDAC9 for the treatment of atherosclerosis in humans.